Lifespan extension by calorie restriction relies on the Sty1 MAP kinase stress pathway

EMBO J. 2010 Mar 3;29(5):981-91. doi: 10.1038/emboj.2009.407. Epub 2010 Jan 14.

Abstract

Either calorie restriction, loss-of-function of the nutrient-dependent PKA or TOR/SCH9 pathways, or activation of stress defences improves longevity in different eukaryotes. However, the molecular links between glucose depletion, nutrient-dependent pathways and stress responses are unknown. Here, we show that either calorie restriction or inactivation of nutrient-dependent pathways induces lifespan extension in fission yeast, and that such effect is dependent on the activation of the stress-dependent Sty1 mitogen-activated protein (MAP) kinase. During transition to stationary phase in glucose-limiting conditions, Sty1 becomes activated and triggers a transcriptional stress programme, whereas such activation does not occur under glucose-rich conditions. Deletion of the genes coding for the SCH9-homologue, Sck2 or the Pka1 kinases, or mutations leading to constitutive activation of the Sty1 stress pathway increase lifespan under glucose-rich conditions, and importantly such beneficial effects depend ultimately on Sty1. Furthermore, cells lacking Pka1 display enhanced oxygen consumption and Sty1 activation under glucose-rich conditions. We conclude that calorie restriction favours oxidative metabolism, reactive oxygen species production and Sty1 MAP kinase activation, and this stress pathway favours lifespan extension.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 1 / metabolism
  • Blotting, Northern
  • Gene Expression Regulation, Fungal
  • Glucose / pharmacology
  • Hydrogen Peroxide / pharmacology
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / physiology*
  • Oxygen Consumption
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • Schizosaccharomyces / drug effects
  • Schizosaccharomyces / genetics
  • Schizosaccharomyces / growth & development*
  • Schizosaccharomyces / metabolism*
  • Schizosaccharomyces pombe Proteins / genetics
  • Schizosaccharomyces pombe Proteins / metabolism
  • Schizosaccharomyces pombe Proteins / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Stress, Physiological / physiology*

Substances

  • 1-tert-butyl-3-naphthalen-1-ylmethyl-1H-pyrazolo(3,4-d)pyrimidin-4-ylemine
  • Activating Transcription Factor 1
  • Phosphoproteins
  • Pyrazoles
  • Pyrimidines
  • Schizosaccharomyces pombe Proteins
  • atf1 protein, S pombe
  • Hydrogen Peroxide
  • Sck2 protein, S pombe
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases
  • sty1 protein, S pombe
  • Glucose